Novel Antimalarial Dihydroartemisinin Derivatives.
Patent, Filed 20 Aug 87, patented 13 Dec 88,
DEPARTMENT OF THE ARMY WASHINGTON DC
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This invention relates to novel dihydroartemisinin derivatives, including their pharmaceutically-acceptable salts, which are therapeutically-effective in the pre-and post-treatment of malarial infections. The novel compounds were prepared in accordance with this invention by treating dihydroartemisinin with an appropriate alcohol, which also contains an ester functional group, under boron trifluoride etherate catalysis at room temperature. Hydrolysis of the ester group with 2.5 Potassium Hydroxide, Methyl Hydroxide gave the corresponding potassium salts which were converted to free acids by acidification. The derivatives were tested in vitro against 2 clones of human malaria, Plasmodium falciparum D-6Sierra Leone clone and W-2Indochina clone. No cross-resistance to the antimalarial agents mefloquine, chloroquine, pyrimethane, sulfadoxine and quinine was observed. In general, the new compounds are more effective against the multi-drug resistant W-2 clone, than the D-6 clone. To overcome the stability problem, applicants carried out the extensive research necessary to make a series of new water-soluble and stable derivatives, in which the carboxylate solubilizing group is on a moiety which is joined to dihydroartemisinin by an ether, rather than an ester linkage. Keywords Patents. KTAW